CN111514126A - Compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders - Google Patents
Compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
The invention discloses a compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disturbance, which comprises the following components: betaine (300-1000 mg/d), calcium gluconate (500-2000 mg/d), folic acid (10-40 mg/d), vitamin B2 (5-15 mg/d), vitamin B6 (5-15 mg/d), vitamin B12 (20-80 μ g/d) and alpha-tocopherol (10-50 mg/d). The formula integrates symptomatic and pathogenic control, and eliminates target spot damage of the current high Hcy state of the organism by relieving ROS damage and the activity reduction of vascular endothelial cells in the aspect of symptomatic; on the aspect of causes, the aim of quickly reducing the Hcy level of blood is fulfilled by comprehensively correcting five biochemical pathways related to folic acid metabolic disorder; in addition, a high-throughput cell experiment and a random double-blind control multicenter volunteer experiment are comprehensively utilized in formula development, and the action range and the toxicity threshold of each component of the formula are accurately detected, so that the dosage of each component has certain tolerance and strong safety, and the formula is suitable for serving as a core formula of a nutritional supplement of a health-care product or a food therapy and is beneficial to development and marketing of subsequent related products.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to a compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders.
Background
Homocysteine (Hcy) is an intermediate product of methionine metabolism in vivo, various metabolic disorders cause abnormal accumulation of Hcy in vivo, and hyperhomocysteinemia (HHcy) can be diagnosed when the plasma Hcy is more than 15 mu mol/L. HHcy produces toxic injury to various tissues and organs such as heart and cerebral vessels and is an independent risk factor for inducing various cardiovascular and cerebrovascular diseases, so that hypertension accompanied with HHcy is called hypertension or H-type hypertension for short, and a large sample study in 6 cities in China shows that the H-type hypertension accounts for about 75 percent in Chinese hypertension patients and is an important type of metabolic diseases.
HHcy is the result of disorder of various metabolic pathways of human bodies, because the bodies have strong capability of maintaining homeostasis, the occurrence of HHcy means that the compensatory capability of related metabolic networks is disordered, and the generated high concentration of Hcy can seriously interfere the structural stability of various sulfhydryl proteins in cells and the elimination of Reactive Oxygen Species (ROS), thereby causing a series of cardiovascular and cerebrovascular injuries. Research shows that the risk of stroke is increased by 59% when the blood Hcy is increased by 5 mu mol/L, so that HHcy is taken as a potential variable risk factor in primary stroke prevention in American stroke journal.
There are five ① methylation pathways among Hcy metabolic pathways, i.e., the methylation of Hcy under the action of vitamin B12, methyl donor N5-methyltetrahydrofolate and methionine synthetase to form methionine, wherein the methyl donor is formed by catalyzing N5 and N10-methyltetrahydrofolate with methyltetrahydrofolate reductase (MTHFR) with vitamin B2 as coenzyme, the alternative pathway of ② methylation is formed by methylation of methionine under the action of betaine-homocysteine methyltransferase with betaine as methyl donor, the ③ transsulfuration pathway is formed by the formation of cystathionine and serine under the action of vitamin B6 and β -cystathionine synthase (CBS) and further cleavage of cystine and α -ketobutyrate, the direct release of ④ Hcy to extracellular fluid, and ⑤ Hcy under the action of Fe3+Or Ca2+Under the catalysis of the heavy metal ions, the self-oxidation metabolism is realized.Abnormality in any of the above metabolic pathways may result in the production of HHcy due to the inhibition of metabolism of Hcy.
The reduction of the blood Hcy has a very important effect on the improvement of the health of people in China, but the existing HHcy prevention and treatment scheme has a plurality of problems and defects, so that the morbidity, cure rate and harm of the HHcy are high throughout the year. For example, in patent nos. CN201115679 and CN200710175651, the use of drugs or drug combinations to prevent and treat HHcy requires long-term administration or even injection of certain drug or drugs, which results in low compliance of intervention subjects, i.e. difficult consistent use due to fear of side effects of long-term use of drugs, and affects intervention effect. Patent application nos. CN201910452229 and CN201710910596 claim that nutrient components for preventing and treating HHcy can be obtained from natural food or vegetables, but the disclosed formula contains 1-10 mg of active iron, and the iron is a core catalyst of fenton reaction, so that hydrogen peroxide generated by HHcy induction can be converted into extremely high oxidative hydroxyl radical, ROS damage and cell iron death caused by HHcy are more serious, and damage of HHcy to heart and brain blood vessels is aggravated.
More importantly, the current Hcy prevention and treatment scheme does not completely consider five pathways of Hcy metabolism at first, so that the Hcy reduction effect of the therapy represented by the mainstream folic acid supplement is poor; in addition, it is currently acknowledged that HHcy mainly damages cardiovascular and cerebrovascular endothelial cells, and previous cell experiments of the inventor prove that HHcy induces vascular endothelial cell iron death, but all treatment schemes searched by the inventor do not specifically protect the vascular endothelial cells induced by HHcy, so that the prevention and treatment effect is poor.
Disclosure of Invention
As a complex metabolic disorder, HHcy treatment preferably covers five major pathways of Hcy metabolism, and is formulated to completely correct the metabolic disorder and prevent vascular endothelial injury. Therefore, on the basis of metabonomics analysis, the compound formula most suitable for preventing and treating HHcy is obtained through long-term cell experiments, animal models and random double-blind control experiment improvement and verification of human volunteers, and the ingredients of the compound formula comprise: betaine (300-1000 mg/d), calcium gluconate (500-2000 mg/d), folic acid (10-40 mg/d), vitamin B2 (5-15 mg/d), vitamin B6 (5-15 mg/d), vitamin B12 (20-80 μ g/d) and alpha-tocopherol (10-50 mg/d). The chemical structures of the components in the formula are clear and definite, the physical and chemical properties are stable, and the theoretical speculation and the experiment prove that the problem of mutual interference does not exist, so that no special requirements are imposed on the preparation method such as the adding sequence of the components and the like.
Compared with the prior art, the invention has the following advantages:
theoretically, the ingredients of the formula of the invention have complex benign interaction, and theoretically, the synergistic effect can be generated.
1. The components of the formula maintain stability mutually: betaine and calcium gluconate are amphoteric compounds which are not easy to oxidize and have high thermal stability, and the stability of lipoic acid, vitamin B2, B6 and alpha-tocopherol in the formula can be maintained; lipoic acid and alpha-tocopherol are both ROS scavengers, but lipoic acid can protect alpha-tocopherol from oxidative inactivation.
2. The ingredients of the formula have a metabolic synergistic effect: the folic acid has synergistic effect with vitamin B2 and B12, and the lipoic acid can promote the folic acid to be metabolized into tetrahydrofolic acid which is a main active ingredient in human body and protect various vitamins in the formula from inactivation; vitamin B2 can be used as coenzyme component for promoting the generation of B6 metabolic active product; betaine, folic acid, B2, B6 can assist lipoic acid to relieve ROS damage caused by Hcy and protect vascular endothelial cells, B12 can assist folic acid and B2 to promote the methylation of Hcy, B12 can assist betaine to promote the methylation alternative pathway of Hcy, and B12 can assist B6 to promote the serine condensation metabolic pathway of Hcy.
3. Promoting the good absorption of the components of the formula: vitamin B6 can promote absorption of B12.
4. The components of the formula can be mutually synergistic: the five major pathways of Hcy metabolism have complex cross-interaction per se to form a metabolic network, and B vitamins in the five major pathways form a metabolic complex group as water-soluble coenzymes, so that the effect is better when the vitamins are taken at one time than when the vitamins are taken respectively, and the phenomenon is called vitamin B family co-fusion phenomenon, so that the vitamin B family co-fusion phenomenon is suitable for being supplemented together to comprehensively correct metabolic disorder. In addition, lipoic acid is a polar and nonpolar two-phase antioxidant, and can form a synergistic effect with alpha-tocopherol to protect cell membranes from being damaged by active oxygen radicals.
Secondly, from the data of cell experiments, the formula of the invention has obvious synergistic effect
For details, see examples 1 and 2, the composite formula has obvious synergistic advantages in cell experiments compared with the single use of folic acid or the formula A on the market.
Third, from the trial data of volunteers, the formula of the invention is obviously better than the main stream prevention and control scheme
In terms of action and effect, statistical analysis is carried out on the basis of obtaining a large amount of data by comprehensively utilizing cell viability experiments, random double-blind comparison of a large sample in multiple centers of volunteers and other experimental methods, and the formula is found to have better effect than that of the formula which only uses folic acid or some patents (see example 2).
Fourthly, in terms of safety, all components of the formula are from accepted metabolic regulation nutrient substances with low toxicity, and the cytotoxicity of the formula is specially checked in a preliminary experiment, so that the use dose is ensured not to exceed 5% of a toxicity threshold; the effect is increased mainly by means of a small dose of the composite formulation. In addition, the action range and the toxicity threshold of each component of the formula are precisely determined, so that the dosage of each component has certain latitude, and the product development and marketing are facilitated.
In an action mechanism, the formula distinguishes symptomatic treatment and symptomatic treatment means by eliminating ROS damage and endothelial cell activity reduction; and the Hcy is considered to be responsible for metabolic disturbance, and the metabolic disturbance is corrected in multiple ways by targeting the whole way of Hcy metabolism by using the compound formula so as to reduce the blood Hcy level. In a word, the formula can comprehensively prevent and treat HHcy, and the overall effect is far greater than the single effect of each component (see the examples).
Detailed Description
The technical embodiments of the present invention will be described in further detail with reference to specific examples.
Example 1 formulation effectiveness and safety assessment experiment based on high throughput cellular experiments
On the basis of earlier stage work, a high-throughput experiment is utilized to screen out the optimal dosage of each component of the formula, and the formula A is formed: betaine (500 mg/d), calcium gluconate (1000 mg/d), folic acid (30 mg/d), vitamin B2 (10 mg/d), vitamin B6 (10 mg/d), vitamin B12 (50 μ g/d) and alpha-tocopherol (20 mg/d).
Based on relevant documents and earlier work of the invention, the corresponding ratio concentration of each component in the formula A is respectively selected (the mass concentration ratio is 50:100:3:1:1:5:2 according to the sequence, the formula A prepared according to the ratio is 1U when the final concentration of betaine in a culture solution is 0.01 mmol/L), the cell viability is determined by a CCK8 method, and T test analysis is carried out on the basis of data of 5 independent experiments; analyzing the range of the effect and the actual effect of the component in the formula by taking the P less than 0.05 as the standard of obvious difference; in order to improve the safety of the formula, the lowest dosage of P & gt 0.01 is taken as the toxicity dosage threshold of the component, and the final concentration data of the formula A are obtained as follows: the effective range is 5-200U, the toxicity threshold is 5000U, which is more than 25 times of the maximum effective dose, and the formula has excellent safety.
Example 2 random double-blind control multicenter volunteer experiment of the present formulation at superior concentrations
In the 3 months to 2019 in 2018, 50 volunteers with high Hhy blood levels (150 people in total, the average age is 48.3 years old, the proportion of men and women is 1.17, the body mass index is 26.10, and the average blood Hhcy is 18.62 mmol/L) detected in three cities of Beijing, Shanghai and Xianyang are respectively selected from each city, and the volunteers with the high Hhy blood levels, the formula A and the medicine-grade folic acid which cannot be distinguished are respectively taken 60 days daily (the formula A is given according to the example 1, the formula B is taken according to the instructions and is taken after lunch), and the volunteer experiments are carried out by adopting a random double-blind control principle, and the results show that the formula A can finally reduce the blood HHy of the volunteers by 51.5 percent averagely and are 2.28 times and 2.04 times of the intervention effect of the simple folic acid and the formula B respectively, and the volunteers who take the formula A and the formula B without intervention report any discomfort and the biochemical treatment, and the blood of the formula B are not reported in addition, No adverse effect was found in blood routine and other examinations.
The above description is only a preferred embodiment of the present invention, and the scope of the present invention is not limited thereto, and any simple modifications or equivalent substitutions of the technical solutions within the scope of the present invention disclosed by the present invention, which can be obviously obtained by those skilled in the art, should also be considered as the scope of the present invention.
Claims (2)
1. A compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders comprises the following components: betaine (300-1000 mg/d), calcium gluconate (500-2000 mg/d), folic acid (10-40 mg/d), vitamin B2 (5-15 mg/d), vitamin B6 (5-15 mg/d), vitamin B12 (20-80 μ g/d) and alpha-tocopherol (10-50 mg/d).
2. The formulation of claim 1 wherein the individual components are of a purity of pharmaceutical grade, no special requirements are imposed on the method of preparation and the relevant manufacturing processes are outside the scope of this patent.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010438447.2A CN111514126A (en) | 2020-05-22 | 2020-05-22 | Compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders |
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| CN202010438447.2A CN111514126A (en) | 2020-05-22 | 2020-05-22 | Compound formula for preventing and treating hyperhomocysteinemia by comprehensively correcting metabolic disorders |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113230273A (en) * | 2021-05-11 | 2021-08-10 | 北京里肯营养科学研究有限公司 | Compound preparation containing choline, B vitamins, folic acid and zinc for preventing and treating hyperhomocysteinemia |
| CN114617266A (en) * | 2022-04-06 | 2022-06-14 | 苏州兰铭医疗科技有限公司 | Multivitamin composition for Parkinson disease patients and application thereof |
-
2020
- 2020-05-22 CN CN202010438447.2A patent/CN111514126A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113230273A (en) * | 2021-05-11 | 2021-08-10 | 北京里肯营养科学研究有限公司 | Compound preparation containing choline, B vitamins, folic acid and zinc for preventing and treating hyperhomocysteinemia |
| CN114617266A (en) * | 2022-04-06 | 2022-06-14 | 苏州兰铭医疗科技有限公司 | Multivitamin composition for Parkinson disease patients and application thereof |
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Application publication date: 20200811 |